Synthesis and evaluation of a ¹⁸F-labeled spirocyclic piperidine derivative as promising σ₁ receptor imaging agent

Several spirocyclic piperidine derivatives were designed and synthesized as σ₁ receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ₁ receptors and subtype selectivity. Particularly for ligand 1'-((6-(2-fluoro-ethoxy)pyridin-3-yl)methyl)-3H-spiro[2-benzofuran-1,4'-piperidine] (2), high σ₁ receptor affinity (K_i = 2.30 nM) and high σ₁/σ₂ subtype selectivity (142-fold) as well as high σ₁/VAChT selectivity (234-fold) were observed. [¹⁸F]2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8-10%, a radiochemical purity of higher than 99%, and specific activity of 56-78 GBq/µmol. Biodistribution studies of [¹⁸F]2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10 µmol/kg) 5 min prior to injection of [¹⁸F]2 significantly decreased the accumulation of radiotracer in organs known to contain σ₁ receptors. Ex vivo autoradiography in Sprague-Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ₁ receptors. These encouraging results prove that [¹⁸F]2 is a suitable candidate for σ₁ receptor imaging with PET in humans.